Myopia is the most common eye disease worldwide and represents a growing public health burden with especially high prevalence in East Asian countries.1–5 According to the global burden of disease region data, the prevalence of myopia in East Asia is 47.0%, higher than 27.1% in Central Europe, 17.0% in Central Asia, and 7.0% in Central Africa. In a recent meta-analysis of 145 studies, the global prevalence of myopia and high myopia is 1,950 million (28.3% of the global population) and 277 million (4.0% of the global population), respectively, and these numbers are estimated to increase to 4,758 million (49.8%) for myopia and 938 million (9.8%) for high myopia by 2050.6 We also predict that 83% of 40- to 50-year-old adults will be myopic, including 15% with high myopia, by 2050 in Singapore.7 Considering the aging effect that young adults with high rates of high myopia will grow older, the pathologic changes due to high myopia are also estimated to increase in future.8
Although the pathophysiology of myopia is not fully understood, it is commonly accepted that both genetic and environmental factors contribute to myopia.9–11 Some genetic loci associated with myopia and high myopia were identified by the CREAM consortium.12–15 Several environmental risk factors for myopia, for example, near work, education, and less outdoor time, were also reported in previous epidemiologic studies.11,16–20
Eye shape has also been receiving increasing attention as a possible biomarker for myopia.
Recent advances in magnetic resonance imaging (MRI) analysis have enabled us to view the entire globe shape and provide comprehensive biometric information. Most previous studies using 3D MRI have demonstrated that the posterior eye shape becomes prolate (or less oblate) with the progress of myopia.21–24 We first discuss how the shape of eyes changes during myopia onset and progression.
Although the association between the elongated eye shape and myopia is well known, it is still poorly understood what kind of stimulation makes eyes to elongate. Several previous studies have hypothesized that peripheral refraction stimulates the eye to get longer, based on the observation that the defocus signal is stronger in the peripheral retina than in its center because there are more neurons in the peripheral area.25–29 Several lines of evidence supporting this possible mechanism were derived from both animal and human studies.26,28–31 However, the recent longitudinal studies failed to prove that peripheral hyperopia led to progression of myopia, suggesting that the influence of relative peripheral hyperopia on myopia development might not be clinically important.32–34 Another hypothesis regarding the mechanism of eye elongation focuses on scleral remodeling. Animal studies have shown that structural, biochemical, and biomechanical changes in sclera cause ocular elongation and high myopia.35–39 In this model, the role of transforming growth factor (TGF)-β signaling is highlighted as a primary mediator of the scleral metabolic changes.40 TGF-β decreases in high myopic eyes and contributes to the major biochemical changes in sclera such as decreased collagen synthesis and reduction in collagen fibral diameter.41 Progressive ocular enlargement may occur with a weakened sclera caused by scleral metabolic changes.
With increased myopia, the retinal shape tends to become steeper near the posterior pole combined with flattening away from the pole with increased myopia. A recent study reported that the steeper retina is associated with a higher risk of vision-threatening myopic traction maculopathy (MTM), such as foveal retinoschisis, foveal retinal detachment, and macular hole.42 This suggests that abnormal eye shape changes can cause not only simple myopia but also various other ocular complications through biomechanical stretching. Accordingly, we will provide an evidence-based update on abnormal eye shapes in pathologic myopia (PM), a severe consequence of myopia that can lead to vision-threatening conditions.
SEARCH STRATEGY FOR IDENTIFICATION OF STUDIES
A comprehensive search was conducted to detect all previous studies related to an eye shape and myopia by searching (1980–2017) the PubMed database. The search terms contained (“myopia” or “high myopia” or “pathological myopia” or “refractive error”) and (“eye shape” or “eyeball shape” or “ocular shape” or “posterior eye shape” or “fundus shape” or “retina shape” or “posterior retinal contour” or “scleral curvature” or “staphyloma” or “retinal optical coherence tomography” or “retinal OCT”). The reference lists of relevant reviews and articles were also included. A total of 402 articles were identified, and more than 100 abstracts were screened by S.M.
IMAGING TECHNIQUES FOR EYE SHAPE
There are a variety of direct and indirect techniques to evaluate ocular size, volume, and shape.43,44 Magnetic resonance imaging has several advantages over previous methods by providing a more direct measurement of the eye shape. Partial coherence interferometry and optical coherence tomography (OCT) imply that emmetropia, a normal eye, is spherical and becomes prolate or less oblate with the progression of myopia.26,29,45–51
Based on the idea that peripheral retinal areas might be of importance in driving refractive status, retinal shapes were evaluated by partial coherence interferometry for more than 10 years.25–29 The retinal steepness was measured using a custom-made optical low coherence interferometer shift in 140 children aged 7 to 11 years over a 30-month interval by Schmid,29 and they revealed that myopic eyes had steeper retinas than emmetropic eyes. However, it must be taken into account that the shape changes described in the studies using partial coherence interferometry are confined to a relatively smaller area, compared with other retina studies using MRI.
Optical coherence tomography can evaluate microscale retinal abnormalities caused by myopic changes, thus providing valuable information. However, because the area visualized by current clinical OCT is limited to a small region of the posterior pole, it can be difficult to identify larger posterior abnormalities such as staphylomas outside the imaged area.
Magnetic resonance imaging has several advantages over previous methods by providing a more direct measurement of the eye shape. Since the advent of this new technology that enables us to globally image the entire eye, MRI has been the imaging tool of choice for morphometric analysis of the entire eye in myopia studies.
Complete 3D ocular models from MRI data provide more comprehensive biometric information and potential diagnostic assessments for clinical use. The newer generation of high-field MRI systems and radio-frequency coil designs has made it possible to acquire volumetric ocular MRI data with high resolution in all 3 dimensions. T2-weighted MRI is able to illustrate the internal eye shape by high-contrast delineation of the vitreous–retina interface; this high-contrast interface can be automatically segmented and meshed to provide a complete 3D surface model. To overcome another concern regarding the limitation of MRI's resolution, spin-echo sequences and local shimming can be used to minimize the risk of spatial distortion.52
One of the disadvantages of MRI is the difficulty to obtain MRI images on a routine basis due to practical and financial limitations. In addition, it is difficult to obtain morphological detail of the posterior pole due to resolution limits.
EYE SHAPE AND MYOPIA
Several studies to evaluate the posterior eye shape change in myopic eyes using 3D MRI have been conducted in children and adults (Table 1). Studies have classified four models of retinal stretching in myopia, classified according to where the myopic change mainly occurred, that is, global expansion, equatorial expansion, posterior polar expansion, and axial expansion.53–55 The first 3 models are based on the findings on spherical surfaces. The last axial expansion model is the combined model of equatorial and posterior pole expansion models, which results in a prolate ellipsoid surface.
Using MRI, our group measured the eye shape of 67 young Asian children aged between 6 and 7 years enrolled in the population-based Strabismus, Amblyopia, and Refractive Error in Singapore (STARS) study.56 The eye surface area, but not the eye volume, was significantly associated with spherical equivalent (SE) (P=0.001). Although nonmyopic eyes conformed to the global expansion model, myopic eyes conformed to the axial expansion model with the eye assuming a prolate shape (P=0.001). However, this study analyzed only a relatively small proportion of myopic children. Ishii et al.24 conducted analysis based on the elliptic Fourier descriptors on T2-weighted MRI images of 105 young Asian children aged 1 month to 19 years, and showed that those aged 7 years or older had a significant correlation between an oblate-to-prolate change and SE (P=0.0063).
These results in the children's study suggest that the developmental pattern of the eyeball shape from oblate to spherical occurs during emmetropization, and that after completing the emmetropization, the eyes tend to become prolate with increased SE.
Compared with the MRI studies in children, the sample sizes of MRI studies in adults have been relatively small.
Pope et al.22 measured the changes in eye dimensions and retinal shapes with various refractive errors in 58 subjects aged 18 to 28 years using T2-weighted 3D MRI and reported that emmetropic retinas were oblate (i.e., steepen away from the vertex), but this oblateness decreased with increasing myopia so that retinas were predicted to become prolate beyond 7 D myopia.
However, another study to evaluate the shape of the posterior vitreous chamber on 55 adult subjects with a mean age of 25 years in the United Kingdom using T2-weighted 3D MRI52 showed that the prolate ellipse posterior chamber shapes were rarely found in myopic eyes. Limitations of both studies are their relatively small sample size and relatively younger ages of their participants. Furthermore, the range of refractive error was narrow in the latter study.
Atchinson et al. reported that with an increase in myopic refractive correction, myopic eyes became much larger in all 3 dimensions, but more so in length (0.35 mm/D) than in height (0.19 mm/D) or in width (0.10 mm/D) in a study of 88 adults aged 18 to 36 years. Almost a quarter of myopic eyes followed the global expansion or axial elongation model exclusively. They suggested that the ability of eyes to expand is much greater in the axial direction because the orbital walls are much closer to the sides of eyes than behind the eyes.53 However, this study had a technical limitation in reconstruction of complete 3D images because they inferred the 3D shape of the eye from a very limited number of 2D sections in 3-mm thick slices. Moriyama et al. compared ocular shapes, symmetry, and pointedness of the posterior pole between 40 emmetropic eyes and 234 high myopia eyes (SE < −8.00 D) using 3D MRI images.57 Although all the emmetropic eyes showed a symmetrical blunt shape and no deformity in horizontal and sagittal planes, almost half of the high myopic eyes had a pointed shape on the posterior pole.
These studies indicate that the dimensions of the eyes increase in all directions as myopia increases in adult eyes, and that increase in length is significantly greater than increase in width and height resulting in prolate shapes.
In summary, the same trend that eye shapes become prolate (or less oblate) with increasing myopia is shown in both children and adults. Although there are individual differences in eye shapes, nonmyopic eyes tend to follow the global expansion model, whereas myopic eyes tend to follow the axial expansion model. In this model, the eye assumes a prolate shape during development of eye length, especially for ages above 7 years old after completing emmetropization.24 The trend of prolate change is considered to become more prominent beyond a certain level of myopia. Furthermore, the eye shape changes to more prolate contribute to steeping retina near the posterior pole with flattering away from the pole. Clinically, the steeper retina is associated with not only myopia but also a higher risk of vision-threatening MTM.42 Thus, an assessment of the eye shape with increased myopia is essential to understand the mechanism and the structural changes in myopia.
According to a previous study, 25% of high myopia will develop PM and 50% of those with PM will have low vision as older adults.58 In 359 Singapore adults aged 40 to 60 years with high myopia worse than −6 diopters in the Singapore Epidemiology of Eye Diseases (SEED) studies, the rate of myopic macular degeneration (MMD) based on fundus photographs was 27% in Malay, 27% in Chinese, and 11% in Indian populations.58 The most common macular lesions were staphyloma (23%) and chorioretinal atrophy (CRA) (19.3%), followed by retinal hemorrhage (0.9%) and choroidal neovascularization (CNV) (0.9%).
Only a limited number of studies investigating eye shapes in high myopia have been reported so far (Table 2).
Eye Shape and Pathological Myopia
Excessive axial elongation of eyes induces pathological changes such as MMD on the posterior pole. Many reports investigated the relationship between the ocular shape and myopic fundus lesions such as myopic CNV, CRA, and MTM. However, their definitions of myopic lesions are not consistent.57,59–61 To develop a common classification system of myopic maculopathy, a new classification was proposed by the Ohno-K in 2015. The META-PM classification defines five categories of MMD based on fundus photographs, and researchers are encouraged to use this classification in future studies. Although only one study has used the META-PM classification so far, we first highlight this study because of its unambiguous definition of CRA (diffuse, patchy macular atrophy), a major myopic lesion in high myopic eyes.
In this recent report using high-resolution 3D MRI on 95 high myopic Chinese subjects aged 12 to 67 years by Xinxing et al.,61 6 distinct categories of ocular characteristics were defined as follows: spheroidal, ellipsoidal, conical, nasally distorted, temporally distorted, and barrel-shaped. Based on the international META-PM classification, C2 and above myopic maculopathy was observed in all barrel-shaped eyes, in 75% of temporally distorted eyes, and 71.4% of nasally distorted and conical eyes. One of the limitations of this study is that the subjects were relatively younger and had less refractive error. However, this study is important because of its first use of the international META-PM classification. Although their definitions of myopic lesions were not uniform, several previous studies had similar consistent results. One study using 3D MRI in 105 subjects with PM showed that almost half of the total eyes had no staphylomas and showed a barrel-shape globe.62 Another study using 3D MRI for 70 eyes63 reported that diffuse, patchy atrophy and macula atrophy were observed more frequently in eyes with irregular curvature (P<0.0001). Moriyama et al.57 examined the frequency of CRA in 234 eyes using 3D MRI images. Chorioretinal atrophy were more frequent in eyes with pointedness of the posterior surface (P=0.03). These are all hospital-based studies and may have a potential sampling bias. In addition, they did not use the standardized grading system for the classification of MMD.
Compared to CRA, myopic CNV and MTM are rare but severe complications in high myopic eyes, and both lead to functional damage such as vision loss once developed. Few studies were conducted to evaluate the relationship between the ocular shape and these myopic lesions using 3D MRI data. According to one study on 70 high myopic eyes,63 myopic CNV and MTM were observed more frequently in eyes with irregular curvature (P=0.004). In another study of 234 high myopic eyes, Moriyama et al.57 reported that MTM were more frequent in eyes with pointedness of the posterior surface (P<0.001) but that CNV was not associated with any eye shapes. The authors suggested that the number of eyes with CNV might not be sufficient for statistical analysis. Another study by the same author60 on 60 high myopic eyes (SE > −8.00 D or AL >26.5 mm) showed that myopic CNV and MTM were not associated with different types of ocular shapes, presumably due to the small sample size.
Although OCT has a limitation in its capture size compared with MRI, interesting results were shown in a few studies to evaluate the shape of the posterior pole.59 Miyake et al. examined 192 eyes using a novel method to analyze the curvature of 12 lines of 9-mm radial OCT scans, and revealed that eyes with myopic CNV tended to have relatively flat posterior poles with smooth surfaces and that eyes with CRA exhibited a steep, curved shape with an undulated surface. Another study with quantitative analysis of OCT images of 40 high myopic eyes showed that MTM occurred more frequently in eyes with a steeper curvature of the area within 3-mm radius circles at the fovea than in eyes with sphere-shaped at the posterior pole (P<0.01).42 The limitations of this study are its clinical setting and its relatively small sample size.
Eye Shape and Staphyloma
Staphyloma is most commonly observed in high myopic eyes, and previous reports revealed that staphyloma was correlated with AL and SE.61,64 Chang et al. examined the prevalence of staphyloma in 359 adults with high myopia (SE < −6.00 D) using 45° fundus photographs. It showed that staphyloma was found more with increased myopia degree: 11.1% in eyes with −6.00 to −7.99 D, 23.8% in eyes with −8.00 to −9.99 D, and 59.0% in eyes with −10.00 D or greater. The risk of staphyloma increased by 1.56 times for each diopter of increasing myopic refractive error (P<0.001).58
Ohno-Matsui62 analyzed 105 subjects with a mean age of 64.3 years by 3D MRI and wide-field fundus imaging, and proposed a new classification of posterior staphyloma based on its location and description. The most frequent type of staphyloma was type I: wide, macular staphyloma (74% of eyes with staphyloma), followed by type II: narrow, macular staphyloma (14%). Guo et al. assessed staphyloma of 95 high myopic Chinese subjects using high-resolution 3D MRI.61 The most common ocular shape in highly myopic eyes with staphyloma was conical shape (45.5%), followed by nasally distorted (31.8%) and barrel-shaped (13.6%), and spheroid was the predominating ocular shape in less severe highly myopic eyes and in eyes without staphyloma. Compared to the spheroidal shape, eyes with deformity such as conical and distorted shape were associated with not only severe myopic maculopathy, but also a risk of staphyloma lesions. It suggests that eye shape also may be an important risk factor for staphyloma.
To summarize, high myopic eyes are not simply elongated, but the posterior sclera of high myopic eyes tend to expand nonuniformly. From the biomechanical view point, severe highly myopic eyes have differences in the biochemical makeup of the scleral collagen content. The extremely thin sclera develops thin irregular scleral curvature, which can lead to vision-threatening pathologic lesions. Although most current treatment strategies against PM have not been effective and costly so far,65 posterior scleral reinforcement (PSR) has been introduced as a possible treatment to increase scleral tissue stiffness and to inhibit excessive axial elongation of highly myopic eyes. Eye shape analysis using high-resolution 3D MRI has a possibility to provide detailed information to detect localized areas of scleral weakness. Wen et al.66 demonstrated that 3D MRI examination was effective to obtain geometric information before and after PSR for preoperative preparation and postoperative assessment. Eye shape analysis is an important new area of research, and detailed investigations are necessary to enhance our understanding of the pathophysiology of staphyloma and PM development.
Multiple lines of evidence have shown that the eye shape change of nonmyopic eyes follows the global expansion model, and that the eye shape change of myopic eyes follows the axial elongation model. Although nonmyopic eyes generally exhibit an oblate shape, the prolate shapes in myopic eyes tend to increase as myopia develops, especially for ages above 7 years old after completing emmetropization.24 And this trend of prolate changes of myopic eyes is considered to become more prominent with aging and further myopia progression, approximately more than −7 to −8 D. The loss of scleral tissue during axial myopia development is predominantly from the region surrounding the posterior pole of sclera compared with the other region of equatorial and anterior sclera.67 Progressive changes of the scleral structure at the posterior pole followed by the excessive axial elongation lead to increased scleral creep and reduced resistance to intraocular pressure. This time-dependent response might contribute to scleral ectasia clearly, resulting in prolate shape.
Eyes with pathologic myopia have abnormal and complex irregular curvatures of the posterior segment of the eyes such as staphyloma and dome-shaped macula. The early stage of pathologic changes can be caused by myopic development, and more deformed eyes may be formed by aging, in line with high prevalence of staphyloma found in people of older age. Once staphyloma develops, a part of the area around the posterior pole is outpouched, causing more mechanical damage, and tends to have visual field defect more frequently and have worse BCVA.
Considering the increasing prevalence rate of PM, it is critically important to detect the earliest pathological changes that pose a risk of vision-threatening conditions and blindness. Although further longitudinal studies are needed, eye shapes may be potential important biomarkers for PM and its complications.
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